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PMID: 15684389 Published · ppublish English Journal Article

Nm23-H1 metastasis suppressor expression level influences the binding properties, stability, and function of the kinase suppressor of Ras1 (KSR1) Erk scaffold in breast carcinoma cells.

Molecular and cellular biology ·Vol. 25 ·No. 4 ·2005-02-00 ·Pages 1379-88

Salerno M, Palmieri D, Bouadis A, Halverson D, Steeg PS

Abstract

Metastatic disease is a significant contributor to cancer patient mortality. We previously reported that the Kinase Suppressor of Ras1 (KSR1) scaffold protein for the Erk mitogen-activated protein kinase pathway coimmunoprecipitated the metastasis suppressor protein Nm23-H1. We now hypothesize that altered expression levels of Nm23-H1 influence the binding properties, stability, and function of the KSR1 scaffold. Increased coimmunoprecipitation of Hsp90 with KSR1 was observed in either stable or transient transfectants of nm23-H1 in MDA-MB-435 human breast carcinoma cells. Similar trends were also observed in the cytoplasmic and nuclear fractions of cells. Cells expressing high levels of Nm23-H1 exhibited increased KSR1 degradation in the presence of either cycloheximide or an Hsp90-directed drug currently in clinical trial, 17-allylamino-17-demethoxygeldanamycin (17-AAG). In agreement with KSR1 degradation data, high-Nm23-H1-expression cells were preferentially inhibited in anchorage-independent colonization assays by 17-AAG. KSR1 scaffold binding patterns are dynamic in both the cytoplasmic and nuclear compartments, modulated by metastasis suppressor expression. Metastasis suppressor expression levels can impact traditional signaling pathways, such as the Erk pathway, resulting in altered tumor cell sensitivity to cancer therapeutics.

MeSH Terms
Benzoquinones Breast Neoplasms/metabolism Cell Fractionation Cell Nucleus/metabolism Cell Proliferation/drug effects Cycloheximide/pharmacology Cytoplasm/metabolism Extracellular Signal-Regulated MAP Kinases/metabolism Female Genes, Tumor Suppressor HSP90 Heat-Shock Proteins/metabolism Humans Lactams, Macrocyclic NM23 Nucleoside Diphosphate Kinases Nucleoside-Diphosphate Kinase/metabolism Protein Binding/drug effects,physiology Protein Denaturation/drug effects Protein Kinase Inhibitors/pharmacology Protein Kinases/metabolism Rifabutin/analogs & derivatives,pharmacology Signal Transduction/drug effects,physiology Tumor Cells, Cultured
Chemicals
Benzoquinones HSP90 Heat-Shock Proteins Lactams, Macrocyclic NM23 Nucleoside Diphosphate Kinases Protein Kinase Inhibitors Rifabutin tanespimycin Cycloheximide Protein Kinases KSR-1 protein kinase Extracellular Signal-Regulated MAP Kinases NME1 protein, human Nucleoside-Diphosphate Kinase
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Salerno Massimiliano
Women's Cancers Section, Laboratory of Pathology, Building 10, Room 2A33, National Cancer Institute, Bethesda, MD 20892, USA. maxsal@mail.nih.gov
Palmieri Diane
Bouadis Amina
Halverson Douglas
Steeg Patricia S
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.25.4.1379-1388.2005
Email
maxsal@mail.nih.gov
Published
2005-02-00
Pages
1379-88
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC548014
Subset
IM
External Links
PubMed source DOI: 10.1128/MCB.25.4.1379-1388.2005 PMC Full Text View journal details
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